At present, angiotensin II receptor antagonists and calcium antagonists are widely used as pharmaceuticals for the treatment or prophylaxis of hypertension, a heart disease, or the like.
Mineralocorticoid receptors (MR) (aldosterone receptors) are known to play an important role in regulating electrolyte balance and blood pressure in the body, and MR antagonists having a steroidal structure such as spironolactone and eplerenone are known to be useful for the treatment of hypertension and heart failure.
Angiotensin II receptor antagonists which are renin-angiotensin system inhibitors are particularly effective in renin-dependent hypertension and exhibit a protective activity against cardiovascular disorders and kidney disorders. Further, calcium antagonists antagonize (inhibit) the function of calcium channels so as to have a natriuretic activity in addition to a vasodilatory activity, and are therefore effective also in fluid retention (renin-independent) hypertension.
Accordingly, it is expected that by using an MR antagonist and an angiotensin II receptor antagonist or a calcium antagonist in combination, multiple causes of high blood pressure can be suppressed simultaneously, and a stable and sufficient therapeutic or prophylactic effect on hypertension is exhibited regardless of the causes of the disease.
Further, also diuretics are widely used as pharmaceuticals for the treatment or prophylaxis of hypertension, a heart disease, or the like. Diuretics are effective in the treatment of hypertension because of their diuretic effect. Therefore, it is expected that by using an MR antagonist and a diuretic in combination, multiple causes of high blood pressure can be suppressed simultaneously because of the diuretic activity of the diuretic, and a stable and sufficient therapeutic or prophylactic effect on hypertension is exhibited regardless of the causes of the disease.
1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (hereinafter referred to as “compound (I)”) is disclosed in PTL 1 and PTL 2, and is known to be useful for treating hypertension, diabetic nephropathy, and the like.
(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl]imidazole-5-carboxylate (hereinafter referred to as “olmesartan medoxomil”) is an angiotensin II receptor antagonist, and is known to be useful as a pharmaceutical for treatment or the prophylaxis of hypertension, a heart disease, and the like (PTL 3).
Olmesartan medoxomil is commercially available as Olmetec (registered trademark) tablet or Benicar®, each of which contains olmesartan medoxomil as an active ingredient in an amount of 5 mg, 10 mg, 20 mg, or 40 mg, and further contains low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, crystalline cellulose, lactose, and magnesium stearate as additives.
Further, 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chloro phenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (hereinafter referred to as “amlodipine”) is a known compound as an excellent calcium antagonist and is useful as a pharmaceutical for the treatment or prophylaxis of hypertension, a heart disease, and the like (PTL 4)
Amlodipine is commercially available as Norvasc (registered trademark) tablets, which contain amlodipine besylate as an active ingredient in an amount of 3.47 mg or 6.93 mg (2.5 mg or 5 mg in terms of amlodipine) and further contains crystalline cellulose, anhydrous calcium hydrogen phosphate, carboxymethyl starch sodium, magnesium stearate, hydroxypropyl methyl cellulose, titanium oxide, talc, and carnauba wax as additives. Further, 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide (hereinafter referred to as “hydrochlorothiazide”) is a known compound as an excellent thiazide-based diuretic and is described in, for example, PTL 5, and the like.